Endogenous Growth Hormone (GH) plays an important role in the establishment (mammogenesis) and maintenance (lactogenesis) of ruminant lactation (Cowie et al. In "Lactation", 123-140 Ed. I. R. Falconer 1971, Vines et al. J. Dairy Sci 60: 1949-1957, 1977).
It is known that serum levels of endogenous GH are greater in high yielding than low yielding cows (Hart et al, Endocr. 77:333-345, 1978) and in animal studies it has been shown that a synergistic effect of GH together with other lactogenic hormones is obtained in the development of the mammary gland (Tucker J. Dairy Sci 64: 6: 1403-1421, 1981). The site of action of GH is less clear, as limited animal studies have failed to show binding of labelled GH to mammary tissue, suggesting GH receptors are not present in the gland in significant concentrations. Recent advances in understanding the mode of action of GH via insulin-like growth factors and the identification of various growth factors in mammary secretions suggest that GH may mediate its effect on the mammary gland via insulin-like growth factors (IGFs). (Phillips et al NEJM 302: 371-378, 1980, Baxter et al J. Clin Endocrinol Metab 58: 955-959, 1984, Corps et al J. Clin. Endocrinol Metab 67; 25-29, 1988) although there is contradictory data (Davis et al. J. Endocrinol 123,33, 1989).
It is not known if these growth factors are produced locally, or transferred from the maternal circulation and what influence maternal and milk levels of these peptides have an initial lactation, maintenance of lactation and neonatal growth.
For many years it has also been known that exogenous GH will significantly increase the milk yield in cattle (Machlin et al. J. Dairy Sci 56: 575-580, 1973) although close arterial infusions of GH into the mammary gland of ruminants does not increase milk yield, suggesting an indirect effect (Mc Dowell et al. Aust J Biol Sciences 40, 181-189. 1987).
The mechanism of GH-potentiated boosting of milk yields remains unknown, although several lines of research suggest that the most likely mode of action is via insulin-like growth factors acting either directly or indirectly. IGFs have now been found in the mammary secretions of various animals and more recently in milk samples from lactating mothers up to 6 months post partum.
While considerable knowledge has thus been obtained recently regarding animal lactation, this knowledge has to date not been extended to the human.
However in the non-ruminant, the role of growth hormone in lactation is much less defined and is likely to be very minor. GH may play a part in mammogenesis, but in lactogenesis the most important controlling hormone seems to be prolactin (Shiu RPC et al. Annu. Rev. Physiol 42:83-96, 1980). Prolactin receptors are present in mammary tissue (Shiu et al. Biochem J 140:301, 1974), indicating a direct effect of prolactin on the breast, and prolactin mediated events such as the incorporation of tritiated leucine into casein are blocked by antibodies to the prolactin receptor. (Shiu et al. Science 192: 259, 1976). Prolactin levels rise during suckling and basal levels are also elevated during the initial weeks of lactation (Noel GL et al. J Clin Endocrinol Metab 38:413-423, 1974). If levels are lowered e.g. by ergot drugs, lactation ceases.
Conversely, neuropharmacologic agents which block inhibition of prolactin release such as Reserpine (11,17-dimethoxy-18-((3,4,5-trimethoxybenzoyl)oxy)yohimban-16-carboxylic acid methyl ester) and Metoclopromide (4-amino-5-chloro-N-((2-diethylamino)ethyl)-2-methoxybenzamide), increase serum prolactin levels with a positive effect on lactation volumes. (Guzman et al. Acta Obstet Gynaecol Scand 58:53-55, 1979). These effects of pharmacologic intervention on prolactin levels and subsequent changes in lactation volumes are mirrored in several pathological conditions seen clinically. In Sheehans syndrome (pituitary failure following childbirth) prolactin levels are considerable diminished, with subsequent failure of affected mothers to establish lactation. Conversely, in situations of prolactin excess, e.g. prolactin-secreting tumours, the clinical presentation is often inappropriate lactation in both sexes. (Kleinberg et al. N. Eng J Medicine, 296:589-600, 1977). In contrast growth hormone levels are low throughout lactation and do not rise with suckling.(See Noel GL et al above). It is also known that ateliotic (GH-deficient) female dwarves lactate normally (See Rimoin DL et al J. Clin Endo Metab. 28,1183-88. 1986). Therefore the weight of evidence supports prolactin as the dominant hormone in human lactogenesis and any role for growth hormone in this situation appears minor.
Failure of normal lactation is a well established entity in man and causes considerable emotional distress to the affected mother. Current treatment options are relatively limited. Available drugs such as Reserpine and Metoclopromide are often used because their pharmacologic actions include stimulating release through dopamine pathways. However they can cause disadvantageous side effects, e.g. sedation and/or hypotension in a significant proportion of mothers and because they are probably, like sulpiride (another procainamide analogue), excreted in breast milk, could have potentially toxic effects for the infant. (See Aono T et al J. Clin. Endocrinol. Metab. 47:675-680, 1978).
Alternative treatment approaches are clearly required. An obvious approach to this problem would be to directly increase maternal prolactin levels by supplementation. Unfortunately recombinant prolactin is not available for a large scale trial of this treatment and pituitary derived prolactin has now been found to be unsafe, following cases of Jacob-Creuzfield disease in children treated with pituitary derived hormones. Recombinant human growth hormone, however, is readily available.
Lactation failure in humans is a common clinical event with serious emotional sequelae. It has been considered to be a significant problem in 5 to 10% of all lactations. In many instances this leads to premature initiation of supplements or total weaning. This is considered to be an inferior child rearing practice and may be harmful to certain infants with an increased risk of gastritis etc. Many affected women are severely emotionally distressed by their perceived inadequacy, thus effecting the parent-child bond. Failure to thrive in infants is not uncommon if the mother refuses to supplement.
There has therefore been a long need for a medicament, which can promote human lactation e.g. when there is a lactation failure after the birth of the child. This is a human problem. For animals like cow and goat, there has only been a need for an increase of the milk production above a normal level.
In EP 317 387 it is suggested that the production of milk and the weight of the new born child as well as the post partum weight gain in animals and in humans will increase, when an effective amount of hGRF is given to the mother before child birth. The animal is treated for a short time (10-20 days). No experiments have been carried out on humans and in the examples only sheep have been used and any effect was probably indirect through stimulation of mammogenesis late in gestation, given the short half life of hGRF.
There is no substantive or direct evidence that in man growth hormone has a significant role in lactogenesis (Rimoin DL et al. J. Clin. Endocrinol Metab. 28:1183-1188, 1968).
There has been no reason to suppose that hGH would be useful in human lactation failure and no one has yet examined the use of hGH for lactation failure in the newly delivered human mother.